Maintenance of leukemia has been demonstrated to be dependent upon a small sub-population of cells within the bulk leukemic population that have self-renewal properties and are termed leukemia-initiating cells (LICs). LICs share mechanistic properties with regular stem cells including a more quiescent nature, which is thought to mediate their resistance to standard chemotherapy-based treatment. Failure to effectively target LICs can result in disease relapse. Chronic Myelogenous Leukemia (CML) is an extensively studied stem cell disorder in which the LIC pool is not always eradicated by current targeted therapy, leading to disease relapse upon drug discontinuation. We have demonstrated that expression of the Promyelocytic Leukemia (PML) tumor suppressor is surprisingly high in both regular hematopoietic stem cells (HSCs) and in CML blasts and that loss of PML expression predicts a more favorable outcome in CML. We subsequently demonstrated that PML plays a key role in maintaining the quiescence and self-renewal properties of HSCs/LICs although the exact molecular mechanisms involved are poorly understood. PML is also known to be pharmacologically inhibited by treatment of cells with arsenic, which specifically decreases the stability of the protein. Taking advantage of this, we have used arsenic-mediated ablation of Pml in a mouse model of CML to successfully target LICs. However, the effectiveness of PML targeting in the clinic needs to be assessed. Therefore, in order to understand the key pathways downstream PML required for LIC maintenance and to translate PML-ablative LIC targeting to the clinic we propose the following Specific Aims: (1) to study the molecular function of PML in quiescent LICs and its role in the cross-talk between LICs and the bone marrow niche; (2) to assess effectiveness of arsenic treatment in more clinically relevant mouse models of CML; (3) to develop a clinical trial of combination arsenic+dasatinib treatment for chronic phase CML. Accomplishment of these aims could greatly improve treatment of patients with CML, possibly allowing discontinuation of therapy after LIC eradication. Further, understanding PML function could provide other therapeutic targets for LIC and cancer stem cell ablation.